Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease

Graft-versus-host disease (GVHD) is a principal cause of morbidity following allogeneic hematopoietic cell transplantation (HCT). Standard therapy for GVHD, high-dose steroids, results in complete responses (CRs) in 35% of patients. Because tumor necrosis factor-α (TNFα) is an important effector of experimental GVHD, we treated patients with new-onset GVHD with steroids plus the TNFα inhibitor etanercept on a previously reported pilot trial (n = 20) and a phase 2 trial (n = 41). We compared their outcomes with those of contemporaneous patients with GVHD (n = 99) whose initial therapy was steroids alone. Groups were similar with respect to age, conditioning, donor, degree of HLA match, and severity of GVHD at onset. Patients treated with etanercept were more likely to achieve CR than were patients treated with steroids alone (69% vs 33%; P < .001). This difference was observed in HCT recipients of both related donors (79% vs 39%; P = .001) and unrelated donors (53% vs 26%; P < .001). Plasma TNFR1 levels, a biomarker for GVHD activity, were elevated at GVHD onset and decreased significantly only in patients with CR. We conclude that etanercept plus steroids as initial therapy for acute GVHD results in a substantial majority of CRs. This trial was referenced at www.clinicaltrials.gov as NCT00141713.

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Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network

Blood ◽

10.1182/blood-2009-03-212290 ◽

2009 ◽

Vol 114 (3) ◽

pp. 511-517 ◽

Cited By ~ 155

Author(s):

Amin M. Alousi ◽

Daniel J. Weisdorf ◽

Brent R. Logan ◽

Javier Bolaños-Meade ◽

Shelly Carter ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Complete Response ◽

Marrow Transplant ◽

Initial Therapy ◽

Phase 2 ◽

Host Disease ◽

Graft Versus Host ◽

Phase 2 Trial ◽

Acute Graft

Abstract Acute graft-versus-host disease (aGVHD) is the primary limitation of allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard initial therapy, yet only 25% to 41% of patients completely respond. This randomized, 4-arm, phase 2 trial was designed to identify the most promising agent(s) for initial therapy for aGVHD. Patients were randomized to receive methylprednisolone 2 mg/kg per day plus etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), or pentostatin. Patients (n = 180) were randomized; their median age was 50 years (range, 7.5-70 years). Myeloablative conditioning represented 66% of transplants. Grafts were peripheral blood (61%), bone marrow (25%), or umbilical cord blood (14%); 53% were from unrelated donors. Patients who received MMF for prophylaxis (24%) were randomized to a non-MMF arm. At randomization, aGVHD was grade I to II (68%), III to IV (32%), and (53%) had visceral organ involvement. Day 28 complete response rates were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival was 47%, 64%, 49%, and 47%, respectively. Cumulative incidences of severe infections were as follows: etanercept 48%, MMF 44%, denileukin 62%, and pentostatin 57%. Efficacy and toxicity data suggest the use of MMF plus corticosteroids is the most promising regimen to compare against corticosteroids alone in a definitive phase 3 trial. This study is registered at http://www.clinicaltrials.gov as NCT00224874.

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Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease

Acta Haematologica ◽

10.1159/000494423 ◽

2018 ◽

Vol 141 (1) ◽

pp. 19-22

Author(s):

Liat Shargian-Alon ◽

Pia Raanani ◽

Uri Rozovski ◽

Tali Siegal ◽

Shlomit Yust-Katz ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Cerebellar Atrophy ◽

Acid Decarboxylase ◽

High Dose ◽

Host Disease ◽

Graft Versus Host ◽

Aged Woman

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient’s condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.

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Review of Haploidentical Hematopoietic Cell Transplantation

Journal of Global Oncology ◽

10.1200/jgo.18.00130 ◽

2018 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Mehreen A. Khan ◽

Qaiser Bashir ◽

Qamar-un-Nisa Chaudhry ◽

Parvez Ahmed ◽

Tariq M. Satti ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Versus Host Disease ◽

Graft Failure ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

High Dose ◽

Unrelated Donor ◽

Post Transplantation ◽

Host Disease ◽

Graft Versus Host

Use of haploidentical (haplo) donors for hematopoietic cell transplantation (HCT) has significantly increased in the last decade. The major advantage with this strategy is universal availability and faster acquisition of the donor, along with affordability and provision of immunotherapy in post-transplantation period. Historically, haplo-HCT was associated with compromised outcomes because of high rates of graft-versus-host disease and graft failure, but after the development of a post-transplantation high-dose cyclophosphamide strategy, which results in selective T-cell depletion, these issues have been addressed to a large extent. Nevertheless, graft failure, high treatment-related mortality due to graft-versus-host disease, infections, delayed immune reconstitution, and disease relapse remain significant concerns. As the experience with haplo-HCTs grows, the clinical outcomes are becoming more at par with those seen with fully matched unrelated donor allogeneic HCTs.

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Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation

Journal of Clinical Oncology ◽

10.1200/jco.2012.45.0247 ◽

2013 ◽

Vol 31 (12) ◽

pp. 1530-1538 ◽

Cited By ~ 140

Author(s):

Rainer Storb ◽

Boglarka Gyurkocza ◽

Barry E. Storer ◽

Mohamed L. Sorror ◽

Karl Blume ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

High Dose ◽

Host Disease ◽

Graft Versus Host

Purpose We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities. Patients and Methods Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years). Results Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM. Conclusion Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.

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